The New Generation of Targeted Therapies for Breast Cancer

The New Generation of Targeted Therapies for Breast Cancer

The article by Drs. Syed and
Rowinsky is well written and
comprehensive. They introduce
several biologic pathways that are important
in breast cancer and focus on
new pharmaceutical agents designed
to disrupt these pathways. Patients and
physicians hope that agents that target
the tyrosine kinase signal transduction
pathways, block tumor angiogenesis,
modulate apoptosis, and inhibit
histone deacetylation will be effective,
nontoxic therapies for breast
cancer. These molecularly targeted approaches
hold promise, but delivering
on this promise requires that we move
beyond histologic characterization of
the disease and rethink the design of
clinical trials.
Molecular Pathology
The most common histologic type
of invasive breast carcinoma is infiltrating
ductal carcinoma. This diagnosis,
however, is achieved by default,
in that such cases of breast cancer do
not have specific histologic features
that allow them to be categorized as
lobular, tubular, mucinous, medullary,
or inflammatory. Indeed, some pathologists
use the term "infiltrating
ductal carcinoma of no special type."
Some of these cancers express receptors
for estrogen, progesterone, and
HER2; others will not. Decades of
clinical trials have demonstrated that
women with metastatic disease with
estrogen-receptor (ER)- and progesterone-
receptor (PR)-negative tumors
have less than a 10% likelihood of
responding to endocrine therapy.
Those without 3+ overexpression of
HER2 have a low likelihood of responding
to trastuzumab (Herceptin).
Thus, two of our most successful targeted
therapies fail patients with tumors
that are negative for the target.
Molecular profiling has the potential
to refine the pathologic diagnosis
of breast cancer, improve prognostic
accuracy, and predict which patients
will respond to specific therapies.[1]
Genomic analysis of human breast
cancers, using complementary DNA
microarrays reveals that what was
morphologically a single entity is, in
fact, several different subtypes of
breast cancer.[2] The ability to analyze
the expression of thousands of
genes simultaneously will help us
identify a molecular signature for
tumors that will predict which pathways
are driving cancer growth and
which should be targeted for optimal
response.
Imatinib mesylate (Gleevec) therapy
in chronic myelogenous leukemia
provided stunning therapeutic
benefit primarily because patients receiving
therapy were positive for the
target of the drug. In order for this
success to be repeated in the development
of targeted therapies for breast
cancer, our biologic understanding
and pathologic classification of the
disease will have to advance as rapidly
as our choice of agents for study.
Molecularly targeted therapies offer
the opportunity to dissect the pathways
that permit cancer growth. The
fact that these pathways are redundant
and interrelated likely explains
the failure of single agents such as
gefitinib (Iressa) to produce significant
response rates in patients with
advanced breast cancer.
It is time to design clinical trials to
evaluate not only whether a new agent
is effective in some women with breast
cancer, but also which women will
benefit, which will not, and why. Clinical
investigators must partner with
patients and pharmaceutical sponsors
to investigate the modulation of targets
of therapy, develop diagnostic
tools for these targets, and identify
how targets in one pathway interact
with those in another. Patients enrolling
in these clinical trials will need to
be educated about the importance of
granting permission for specialized
analysis of their tumor samples, and
how the information gained will improve
therapy for all diagnosed with
breast cancer.
Clinical Trial Design
Molecular diagnostic and therapeutic
breakthroughs are challenging our
current clinical research methodologies.
Careful selection of patients with
disease expressing the target of therapy
is necessary to prevent unrecognized
molecular heterogeneity from
resulting in an underpowered, falsely
negative study of a new agent.[3] The
traditional therapeutic end points of
clinical trials include increasing overall
survival, regressing tumor lesions
in association with clinical benefit, and
palliating disease-related symptoms.
Studies evaluating molecularly targeted
agents also need to determine
whether the pathway targeted is modulated
by the drug. Most breast cancer
growth results from multiple
genetic aberrations, and targeting a
single pathway is unlikely to result in
a dramatic response. Rather, responses
are likely to require combinations
of targeted therapies that block various
interrelated signals in multiple
pathways. Assessing a new agent's
ability to modulate its target is an additional
important end point of the
clinical trial evaluating its efficacy.
The biologic pathways important
in carcinogenesis and disease progression
are clearly complex, interactive,
and can become resistant to therapy
via multiple mechanisms. This challenges
us to define effective combinations
of targeted therapy. Preclinical
work has identified cross-talk between
the HER2- and ER-signaling pathways
as a potential mechanism of resistance
to tamoxifen. However, numerous retrospective
reviews have yielded mixed
results regarding the impact of HER2
overexpression on response to tamoxifen
therapy.
The impact of HER2 may be modulated
by the ER-coactivator AIB1
(SRC-3). Signaling through the
HER2-receptor pathway activates
AIB1 by phosphorylation. Analysis
of the relationship between ER, HER2,
and AIB1 in a series of patients treated
with adjuvant tamoxifen reveals
that patients with high HER2 expression
and high AIB1 levels had poor
disease-free survivals, whereas those
with high HER2 but low AIB1 expression
had favorable disease-free
survivals.[4] The mixed results regarding
tamoxifen resistance in ER-positive
and HER2-overexpressing tumors
may result from analysis of patients
heterogeneous for AIB1. Dissection
of the HER2- and ER-receptor crosstalk
pathways supports the combination
of endocrine therapy and
inhibitors of signaling through the
HER1 and HER2 pathways, such as
gefitinib (Iressa)

Disclosures

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.